Memory dysfunction is one of the earliest and most debilitating features of Alzheimer's disease (AD). To eventually improve or reverse memory dysfunction, and to understand why it is so prominently involved in AD, it will be necessary to better understand mechanisms underlying memory. Long- term potentiation (LTP) is a use-dependent form of synaptic plasticity that is of great interest as part of the cellular basis of memory storage. It is a sustained increase in synaptic efficacy. As a step in identifying its underlying mechanisms, the goal of this project is to test the hypothesis that LTP is not a unitary process, but consists of 4 distinct components. Identification of its components will be followed in the future by further study of the mechanisms underlying each component, as well as how they may be altered by aging and in AD. Extracellular and whole-cell patch clamp recordings will be made from area CA1 in the rat hippocampal slice preparation. Short-term potentiation (STP) is an increase in synaptic efficacy that returns to baseline in approximately 15 minutes. It has been assumed to be a decremental form of LTP induced by subthreshold stimulation. Preliminary data, however, suggest that STP may be a separately expressed component of plasticity. Specific Aim 1 is to test the hypothesis that STP is a separate, but related, component of potentiation from LTP by comparing five steps in STP and LTP induction and expression for areas of overlap and difference. Several types of experiments have suggested that LTP may consist of early (< 1/2-2hrs) and late phases. Preliminary data suggests that early LTP expression alters paired-pulse facilitation (PPF), a presynaptic form of potentiation, suggesting that early LTP expression includes the presynaptic locus. Specific Aim 2 is to use PPF to test the hypothesis that sustained LTP consists of two components: an early, second messenger mediated, presynaptic component, and a late postsynaptic component. Long-term depression (LTD) is a sustained decrease in synaptic efficacy that may extend the capacity for learning or underlie forgetting. Its underlying mechanism may simply be a reversal of LTP, or it may be a separate component of synaptic plasticity. Preliminary data suggest that LTD increases PPF suggesting that its loci of expression, like LTP, includes the presynaptic site. Specific Aim 3 is to test the hypothesis that LTP and LTD are two independent components of synaptic plasticity by examining two interactions between them, and their effects on PPF. If LTP consists of several components, it would be important to identify and characterize them because each might provide unique sites for therapeutic intervention in synaptic plasticity and memory.